Capello Astrid, Moons Leon M G, Van de Winkel Anouk, Siersema Peter D, van Dekken Herman, Kuipers Ernst J, Kusters Johannes G
Department of Gastroenterology and Hepatology, Erasmus Universiry Medical Center, Rotterdam, The Netherlands.
Am J Gastroenterol. 2008 Jun;103(6):1510-6. doi: 10.1111/j.1572-0241.2008.01908.x. Epub 2008 May 28.
Barrett's esophagus (BE) is a premalignant condition of the esophagus. It is a consequence of mucosal injury from chronic gastroesophageal reflux in which bile acids are an important toxic component. The farnesoid X receptor (FXR) is a nuclear receptor involved in the regulation of bile acid synthesis, transport, and absorption. FXR activation is also involved in the induction of the innate immune response. This suggests that FXR is involved in the pathogenesis and the inflammation seen in BE.
mRNA levels of FXR and the FXR-regulated genes, ileal bile acid-binding protein (IBABP), small heterodimer partner (SHP), and chemokines interleukin (IL)-8 and macrophage inflammatory protein 3 alpha (MIP3 alpha), were determined by real time-polymerase chain reaction (RT-PCR). Protein expression was determined by immunohistochemistry.
FXR was not expressed in squamous epithelium of healthy subjects (N = 7), but was present in both squamous and columnar epithelium of BE patients. Compared to the squamous epithelium of BE patients, their columnar epithelium displayed a 2.3-fold (P= 0.02) increase in FXR mRNA. Also, IBABP (2.2-fold; P= 0.0029), SHP (2.7-fold; P= 0.007), IL-8 (1.5-fold; P= 0.04), and MIP3 alpha (1.7-fold; P= 0.019) transcription levels were increased. Exposure of esophageal cell line TE7 to deoxycholic acid (DCA) resulted in a similar induction. The induction was abolished by the FXR antagonist guggulsterone.
Expression levels of the bile acid receptor FXR, the bile acid metabolism genes IBABP and SHP, and the chemokines IL-8 and MIP3 alpha are increased in Barrett's epithelium. The in vitro induction of FXR by DCA suggests that bile acids can actively induce the inflammatory response in BE by recruiting immune cells.
巴雷特食管（BE）是食管的一种癌前病变。它是慢性胃食管反流导致黏膜损伤的结果，其中胆汁酸是重要的毒性成分。法尼酯X受体（FXR）是一种核受体，参与胆汁酸的合成、转运和吸收调节。FXR激活还参与先天免疫反应的诱导。这表明FXR参与了BE的发病机制和炎症过程。
通过实时聚合酶链反应（RT-PCR）测定FXR及FXR调节基因、回肠胆汁酸结合蛋白（IBABP）、小异二聚体伴侣（SHP）以及趋化因子白细胞介素（IL）-8和巨噬细胞炎性蛋白3α（MIP3α）的mRNA水平。通过免疫组织化学测定蛋白表达。
FXR在健康受试者（N = 7）的鳞状上皮中未表达，但在BE患者的鳞状上皮和柱状上皮中均有表达。与BE患者的鳞状上皮相比，其柱状上皮中FXR mRNA增加了2.3倍（P = 0.02）。此外，IBABP（2.2倍；P = 0.0029）、SHP（2.7倍；P = 0.007）、IL-8（1.5倍；P = 0.04）和MIP3α（1.7倍；P = 0.019）的转录水平也增加。食管细胞系TE7暴露于脱氧胆酸（DCA）导致类似的诱导作用。FXR拮抗剂孕二烯酮可消除这种诱导作用。
胆汁酸受体FXR、胆汁酸代谢基因IBABP和SHP以及趋化因子IL-8和MIP3α在巴雷特上皮中的表达水平升高。DCA在体外对FXR的诱导表明，胆汁酸可通过募集免疫细胞在BE中积极诱导炎症反应。
